Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes

Amy E. Lovett-Racke, Anne E. Rocchini, Judy Choy, Sara C. Northrop, Rehana Z. Hussain, Robert B. Ratts, Devanjan Sikder, Michael K. Racke

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNγ production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the IFNγ and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.

Original languageEnglish (US)
Pages (from-to)719-731
Number of pages13
JournalImmunity
Volume21
Issue number5
DOIs
StatePublished - Nov 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Lovett-Racke, A. E., Rocchini, A. E., Choy, J., Northrop, S. C., Hussain, R. Z., Ratts, R. B., Sikder, D., & Racke, M. K. (2004). Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immunity, 21(5), 719-731. https://doi.org/10.1016/j.immuni.2004.09.010